Mutations that replace aromatic side chains promote aggregation of the Alzheimer's Aβ peptide.
Mutations that replace aromatic side chains promote aggregation of the Alzheimer's Aβ peptide.
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DOI：
10.1021/bi200268w
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发表时间：
2011-05-17
期刊：
影响因子：
2.9
通讯作者：
Hecht MH
中科院分区：
文献类型：
--
作者：
Armstrong AH;Chen J;McKoy AF;Hecht MH
多肽聚集成淀粉样原纤维与许多人类疾病有关。由于这些纤维-或聚集途径上的中间体-在疾病的病因学中起着重要作用，因此已经花费了相当大的努力来理解氨基酸序列的哪些特征促进聚集。被怀疑直接聚集的一个特征是芳香族残基的π-堆叠。这种π-堆积相互作用也被提出作为已知抑制聚集的各种芳族化合物的靶标。在阿尔茨海默氏病的情况下，野生型淀粉样蛋白β（Aβ）肽中的芳香族侧链Phe 19和Phe 20已被牵连。为了明确测试这些侧链的芳香性是否在聚集中起作用，我们用亮氨酸或异亮氨酸替换了这两个苯丙氨酸侧链。这些残基具有与Phe相似的大小和疏水性，但不能进行π-堆积。硫磺素-T荧光和电子显微镜表明，取代残基19和20的亮氨酸或异亮氨酸没有防止聚集，而是增强淀粉样蛋白的形成。进一步的实验表明，芳香族聚集抑制剂对Aβ42的Ile-和Leu-取代形式与对野生型Aβ一样有效。这些结果表明，芳香族π堆积相互作用对于Aβ聚集或抑制Aβ聚集并不关键。
The aggregation of polypeptides into amyloid fibrils is associated with a number of human diseases. Because these fibrils – or intermediates on the aggregation pathway – play important roles in the etiology of disease, considerable effort has been expended to understand which features of the amino acid sequence promote aggregation. One feature suspected to direct aggregation is the π-stacking of aromatic residues. Such π-stacking interactions have also been proposed as the targets for various aromatic compounds that are known to inhibit aggregation. In the case of Alzheimer’s disease, the aromatic side chains Phe19 and Phe20 in the wild-type amyloid beta (Aβ) peptide have been implicated. To explicitly test whether the aromaticity of these side chains plays a role in aggregation, we replaced these two phenylalanine side chains with leucines or isoleucines. These residues have similar sizes and hydrophobicities as Phe, but are not capable of π-stacking. Thioflavin-T fluorescence and electron microscopy demonstrate that replacement of residues 19 and 20 by Leu or Ile did not prevent aggregation, but rather enhanced amyloid formation. Further experiments showed that aromatic inhibitors of aggregation are as effective against Ile- and Leu-substituted versions of Aβ42 as they are against wild type Aβ. These results suggest that aromatic π-stacking interactions are not critical for Aβ aggregation or for the inhibition of Aβ aggregation.
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